DUX4-stimulated genes define the antiviral response to herpesviruses in human trophoblasts

The placenta serves as a barrier against the vertical transmission of viruses, due to the protective functions of fetal-derived trophoblasts. Although some antiviral programs of trophoblasts are well-documented, our understanding of how trophoblasts respond to teratogenic viruses remains incomplete. To address this, we profiled the transcriptional responses of human trophoblast organoids to seven teratogenic viruses. We discovered that herpesviruses including HSV-1, HSV-2, and HCMV did not trigger an interferon (IFN) response but instead induced the expression of DUX4 and downstream target genes, termed DUX4-stimulated genes (DSGs). This program was uniquely, highly expressed in trophoblasts. Through single-cell RNA sequencing, we defined the trophoblast response to DUX4 and demonstrated that this program defines cells with low viral transcripts following HSV-1 infection. Similar to the IFN-stimulated genes, we observed that many DSGs with diverse predicted functions exhibited anti-herpesvirus activity. These findings establish DUX4 and DSGs as a critical antiviral defense mechanism in trophoblasts.